アポモルフィン

DEA NFLIS-Drug Category -> Narcotics

Pharmaceuticals -> Listed in ZINC15

log Kow = 2.30

3.1

MINUTE, WHITE OR GRAYISH WHITE, GLISTENING CRYSTALS OR WHITE POWDER; ODORLESS; SOLN ARE NEUTRAL TO LITMUS; LEVOROTATORY IN DIL ACID; 1 G SOL IN 50 ML WATER, IN ABOUT 50 ML ALCOHOL, & IN ABOUT 20 ML WATER @ 80 °C; PPT BY TANNIC ACID & OTHER ALKALOIDAL PRECIPITANTS & DECOMP BY OXIDIZING AGENTS. /HCL/

Sol in alcohol, acetone, chloroform; slightly sol in water, benzene, ether, petroleum ether

Slightly soluble in hydrochloric acid, ligand; soluble in ethanol, ethyl ether, acetone, benzene, chloroform, alkalies

In water, 1.66X10+4 mg/L at 16 °C

5.10e-01 g/L

Breastfeeding; Lactation; Milk, Human; Antiparkinson Agents; Dopamine Agents; Dopamine Agonists; Emetics; Gastrointestinal Agents

Pharmaceuticals

195 °C (decomposes)

MP: 127-128 °C; specific optical rotation: -88 deg at 24 °C/D (c = 1.12 in 0.1 N HCl) /Diacetate ester/

Small crystals (usually hemihydrate). Decomposes and turn green on exposure to light and air. Specific optical rotation -48 deg at 25 °C/D ( c = 1.2). pH of aqueous solution (1 in 300) = 4.8; One gram dissolves in 50 mL water, 17 mL water at 80 °C, 50 mL alcohol. Very slightly soluble in chloroform and ether. /Hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl apomorphine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Apomorphine hydrochloride/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist class (including, for example, ondansetron, granisetron , dolasetron, palonosetron, and alosetron) is contraindicated.

Potential pharmacologic interaction (additive sedative and hypotensive effects) with alcohol. Potential pharmacologic interaction with CNS depressants (additive sedative effects).

Hypotensive Agents and Vasodilators: Potential pharmacologic interaction (additive hypotensive effects); use with caution. Hypotension, myocardial infarction, pneumonia, serious falls, and bone and joint injuries reported more frequently in patients receiving concomitant antihypertensive drugs or vasodilators. The mechanism underlying many of these events is unknown, but may be associated with hypotension.

Potential pharmacologic interaction (reduced efficacy of apomorphine) when apomorphine is used with certain antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide. Patients with major psychosis receiving certain antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes) should receive dopamine agonists only if benefit outweighs risk.

For more Interactions (Complete) data for APOMORPHINE (6 total), please visit the HSDB record page.

Apomorphine has not been reported to cause serum aminotransferase elevations or clinically apparent acute liver injury, but its use has been limited and is typically given in low doses for a limited period of time. Thus, if apomorphine causes liver injury it must be rare.

The precise mechanism of action of apomorphine as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors within the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits induced by lesions in the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates.

/SIGNS AND SYMPTOMS/ This study was undertaken to ascertain the histopathology and etiology of cutaneous nodules observed in Parkinson's patients treated with continuous subcutaneous apomorphine. Ten patients were recruited, answered questionnaires, and underwent skin biopsies and full blood count, and nine were patch tested to apomorphine and its preservative. Six had serum IgE levels measured. A florid panniculitis was seen in all biopsies; five were predominantly eosinophilic, three lymphocytic and two neutrophilic; in seven cases the panniculitis was mixed and in three it was septal. Patch testing was universally negative and the IgE levels were normal.

/SIGNS AND SYMPTOMS/ A rarely reported motivation for apomorphine abuse (escalation of dose beyond prescribed frequency) is the use of apomorphine to attempt to avoid all symptoms of all "off" events when "off" events occur frequently. A second, rarely reported, motivation for apomorphine abuse is a psychosexual reaction related to the stimulation of penile erection and increase in libido. Adverse events that have been reported in males with overuse include frequent penile erections, atypical sexual behavior, heightened libido, dyskinesias, agitation, confusion, and depression. No studies have been conducted to evaluate the potential for dependence when apomorphine is used as acute (rescue) treatment of "off" episodes in the patients with "on/off" or "wearing-off" effects associated with late stage Parkinson's disease.

/SIGNS AND SYMPTOMS/ Increased incidence of confusion, hallucinations, serious adverse events (life-threatening events or events resulting in hospitalization and/or increased disability), falls, cardiovascular events, respiratory disorders, and GI events in geriatric individuals relative to younger adults.

/CASE REPORTS/ A similar pattern of psychosexual disorders has been observed after long-term treatment with levodopa therapy in four male parkinsonian patients treated with apomorphine for severe on-off motor fluctuations. An acute episode in each case had led them to the hospital in the context of a psychiatric emergency (after punishable sexual acts in two cases). In each case, this episode had been preceded by an increase of self-administered apomorphine, whereas other antiparkinsonian drugs remained unchanged. Questioning had revealed psychosexual disturbances as early as the onset of apomorphine treatment, which tended to progressively worsen with the number of apomorphine daily doses. A decrease in the dosage of apomorphine had been followed by the improvement of the psychiatric condition without worsening of the motor status. Recurrence of psychiatric disorders with similar features had been observed when two patients again increased the number of apomorphine daily injections. The absence of somatic manifestations when apomorphine treatment was withdrawn or reduced, with persistence of psychosexual disturbances, could suggest a psychological dependence from the drug.

For more Human Toxicity Excerpts (Complete) data for APOMORPHINE (7 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

apomorphine

DILI Negative

Subcutaneous

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Neurotoxicity/ It has been proposed that apomorphine and other dopamine receptor agonists might induce neurotoxicity mediated by their quinone and semiquinone oxidation derivatives. The aim of the present study was to evaluate the possible neurobehavioral effects of apomorphine and its oxidation derivative, 8-oxo-apomorphine-semiquinone (8-OASQ). Adult female Wistar rats were treated with a systemic injection of apomorphine (0.05 or 0.5 mg/kg) or 8-OASQ (0.05 or 0.5 mg/kg) 20 min before behavioral testing. Apomorphine and 8-OASQ induced differential impairing effects on short- and long-term retention of an inhibitory avoidance task. Apomorphine, but not 8-OASQ, dose-dependently impaired habituation to a novel environment. The memory-impairing effects could not be attributed to reduced nociception or other nonspecific behavioral alterations, since neither apomorphine nor 8-OASQ affected footshock reactivity or behavior during exploration of an open field. The results suggest that oxidation products of dopamine or dopamine receptor agonists might induce cognitive deficits.

/GENOTOXICITY/ Apomorphine was mutagenic in the in vitro bacterial Ames test and the in vitro mammalian mouse lymphoma assay. Apomorphine was also clastogenic ... in the in vitro mouse lymphoma assay. Apomorphine was negative in the in vivo micronucleus assay in mice.

/GENOTOXICITY/ /It was/ investigated whether systemic injection of apomorphine and its oxidation derivative 8-oxo-apomorphine-semiquinone (8-OASQ) could induce DNA damage in mice brain, using the single-cell gel assay. 8-OASQ induced DNA damage in the brains at 1 and 3 hr, but not at 24 hr after treatment whereas apomorphine induced a slight increase in brain DNA damage frequency at 3 hr after treatment, suggesting that both drugs display genotoxic activity in brain tissue.

/ALTERNATIVE and IN VITRO TESTS/ ... Apomorphine cytotoxicity /was investigated/ by incubating cultures of rat glioma C6 cells and primary cultures of neurons with different concentrations of the drug. Apomorphine-promoted cell death was proportional to its concentration and was time-dependent. The ED(50) of apomorphine on C6 cell death after 48 hr was about 200 uM. The cytotoxic effects induced by apomorphine were correlated to its autoxidation, which leads to the formation of reactive oxygen species, semiquinones, quinones, and a melanin-like pigment. C6 cells that underwent treatment with 400 uM apomorphine for 6 hr displayed features of necrosis, including loss of membrane integrity, degeneration of mitochondria, and DNA fragmentation. Thiols, such as cysteine, N-acetyl-L-cysteine, and glutathione, significantly protected cultured neurons and C6 cells against apomorphine-induced cytotoxicity. Thiols also inhibited apomorphine autoxidation. These data strongly suggest that apomorphine cytotoxicity towards neurons and C6 cells results from an intracellular oxidative stress.

For more Non-Human Toxicity Excerpts (Complete) data for APOMORPHINE (8 total), please visit the HSDB record page.

The commercially available formulation of apomorphine hydrochloride injection contains sodium metabisulfite, which can cause serious allergic-type reactions in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is probably low, but in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis. Sulfite sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and noncardiogenic pulmonary edema if they occur. /Opiates and opioids/

Specific drugs and antidotes: Naloxone is a specific opioid antagonist with no agonist properties of its own; large doses may be given safely. ... Caution: The duration of the effect of naloxone (1-2 hours) is shorter than that of many opioids. Therefore, do not release a patient who has awakened after naloxone treatment until at least 3-4 hours has passed since the last dose of naloxone. In general, if naloxone was required to reverse opioid-induced coma, it is safer to admit the patient for at least 6-12 hours of observation. Nalmefene is an opioid antagonist with a longer duration of effect (3-5 hours). ... /Opiates and opioids/

Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. ... /Opiates and opioids/

Enhanced elimination. Because of the very large volumes of distribution of the opioids and the availability of an effective antidotal treatment, there is no role for enhanced elimination procedures. /Opiates and opioids/

For more Antidote and Emergency Treatment (Complete) data for APOMORPHINE (7 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl apomorphine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Apomorphine hydrochloride/

N - Nervous system

G - Genito urinary system and sex hormones

QN - Nervous system

QV - Various

QG - Genito urinary system and sex hormones

Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with [trimethobenzamide] may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months.

Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown.

The exact mechanism of action of apomorphine hydrochloride in the treatment of Parkinson's disease has not been fully elucidated but may involve stimulation of postsynaptic dopamine D2 receptors within the caudate-putamen in the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits associated with neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ([MPTP])-induced lesions in the ascending nigrostriatal dopaminergic pathway in primates.

Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist that is structurally and pharmacologically related to dopamine. In in vitro studies, apomorphine hydrochloride demonstrated a higher affinity for the dopamine D4 receptor than for dopamine D2, D3, or D5 receptors. Apomorphine hydrochloride binds with moderate affinity to alpha-adrenergic (alpha1D, alpha2B, alpha2C) receptors but has little or no affinity for dopamine D1 receptors, serotonergic (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C) receptors, beta1- or beta2-adrenergic receptors, or histamine H1 receptors. /Apomorphine hydrochloride/

The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes.

The mean terminal elimination half-life is about 40 minutes (range about 30 to 60 minutes).

Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug.

Routes of apomorphine metabolism in humans are not known. Potential metabolic routes include sulfation, N-demethylation, glucuronidation, and oxidation.1 Apomorphine undergoes rapid auto-oxidation in vitro. Cytochrome P-450 (CYP) enzymes play a minor role in the metabolism of apomorphine. In vitro studies have suggested that apomorphine may be metabolized by COMT. Data from in vivo studies indicate that apomorphine is not metabolized by COMT.

Hepatic Half Life: 40 minutes (range 30 - 60 minutes)

N21FAR7B4S

APOMORPHINE

Mechanisms of Action [MoA] - Dopamine Agonists

Established Pharmacologic Class [EPC] - Dopaminergic Agonist

Apomorphine is a Dopaminergic Agonist. The mechanism of action of apomorphine is as a Dopamine Agonist.

Agents that cause vomiting. They may act directly on the gastrointestinal tract, bringing about emesis through local irritant effects, or indirectly, through their effects on the chemoreceptor trigger zone in the postremal area near the medulla.

Drugs that bind to and activate dopamine receptors.

Apomorphine has a plasma Tmax of 10-20 minutes and a cerebrospinal fluid Tmax. The Cmax and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported.

Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine.

The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L.

The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h.

The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 - 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 to 20 minutes later.

Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose range of 2 to 8 mg following a single subcutaneous injection of apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease. /Apomorphine hydrochloride/

... has been used for /powerful emetic/ effect in acute poisoning

THERAP CAT: Antiparkinsonian; emetic. In treatment of male erectile dysfunction

THERAP CAT (VET): Emetic

MEDICATION (VET)

MEDICATION

Use (kg; approx.) in Germany (2009): >10

BY HEATING MORPHINE IN A CLOSED TUBE WITH A GREAT EXCESS OF HCL FOR 2 OR 3 HR @...140-150 °C. THE ELEMENTS OF ONE MOLE OF WATER ARE ABSTRACTED FROM MORPHINE, RESULTING IN A CHANGE IN MOLECULAR STRUCTURE. UPON COOLING, CRUDE APOMORPHINE HYDROCHLORIDE CRYSTALLIZES OUT, BEING LESS SOL IN HCL THAN IN WATER. /HCL/

Synthetic opiate obtained by treating morphine with concentrated HCl.